Glutathione transferase arene oxides

The latter reaction sequence was of importance since addition of the thiol glutathione to arene-oxide intermediates under control of hepatic glutathione-S-epoxide transferase enzyme(s) is a very important metabolic transformation. It would appear probable that most of the structures of the arene oxide-glutathione adducts (premercapturic acids) reported in the literature before 1975 are incorrect with respect to the position of the hydroxy and thioether substituents (they should now be reversed). Addition of thiomethoxide anion to arene oxide 70 may occur via 1,6- and 1,4-addition, although one of these thioether adducts could also be accounted for by the alternative arene-oxide intermediate obtained from an oxygen-walk. Styrene 3,4-oxide (S3) has been observed to react with ethanethiol to yield three adducts which appear to aromatize to three isomeric ethylthiostyrenes without the formation of episulphonium intermediates. ... 

Foureman GL, Hernandez O, Bhatia A, et al. The stereoselectivity of four hepatic glutathione S-transferases purified from a marine elasmobranch (Raja erinacea) with several K-region polycyclic arene oxide substrates. Biochim Biophys Acta 1987 914(2) 127-135. 

The intracellular nucleophile glutathione (GSH y-Glu-Cys-Gly) acts as a protective mechanism against electrophilic insults and may be present at concentrations of up to 10 mM [26]. The reaction of glutathione with a non-polar compound bearing an electrophilic carbon, nitrogen or sulfur atom may be mediated enzymatically by glutathione-S-transferase (GST), with typical substrates being species such as arene oxides, quinones and a,P-unsaturated carbonyl compounds. 

Sulfur nucleophiles such as thiolate anion generally appear near the top of the nucleophi-licity scale and thus readily attack oxepins (Scheme 20). While adduct formation between oxepin (7) and thiols occurs spontaneously upon mixing (74JA6929), a similar reaction between the naturally occurring tripeptide thiol, glutathione, and oxepin-arene oxide intermediates formed during mammalian metabolism is catalyzed by a glutathione epoxide transferase. 

Glutathione conjugation Glutathione (GSH) GSH-S-transferase (cytosol, microsomes) Epoxides, arene oxides, nitro groups, hydroxylamines Acetaminophen, ethacrynic acid, bromobenzene... 

As has been stated before, oxirane derivatives are formed as intermediates during metabolic oxidations at carbon-carbon double bonds. These epoxides (arene oxides) undergo spontaneous isomerization to phenols, or enzymic hydration via epoxide hydrase to trans- dihydrodiols, or reaction with reduced glutathione (GSH) via specific GSH-transferases to the corresponding conjugates (Scheme 11), which eventually appear in urine... 

The 2-oxoacid p-hydroxyphenylpyruvate is decar-boxylated by the action of a dioxygenase (Eq. 18-49). The product homogentisate is acted on by a second dioxygenase, as indicated in Fig. 25-5, with eventual conversion to fumarate and acetoacetate. A rare metabolic defect in formation of homogentisate leads to tyrosinemia and excretion of hawkinsin97 a compound postulated to arise from an epoxide (arene oxide) intermediate (see Eq. 18-47) which is detoxified by a glutathione transferase (Box 11-B). 

Comparison of the reactivities of benzene oxides, naphthalene oxides, phenanthrene oxides, and arene oxides derived from benzo [a] pyrene and 7,12-dimethylbenz[a] anthracene with hepatic glutathione S-epoxide transferase showed that benzene oxides without electron-withdrawing groups are poor substrates as also are polycyclic arene oxides. Only naphthalene oxide was a good substrate. 

The epoxidation of aldrin to dieldrin is an example of the metabolic formation of a stable epoxide (Figure 10.1A), while the oxidation of naphthalene was one of the earliest understood examples of an epoxide (arene oxide) as an intermediate in aromatic hydroxylation (Figure 10.1B). The arene oxide can rearrange nonenzy-matically to yield predominantly 1-naphthol, can interact with the enzyme epoxide hydrolase to yield the dihydrodiol, or can interact with glutathione -transferase to yield the glutathione conjugate that ultimately is metabolized to a mercapturic acid. This reaction is also of importance in the metabolism of the insecticide carbaryl, which contains the naphthalene nucleus. 

The assay method described by Eaton and Stapleton (1989), measures the activities of both cytosolic glutathione 5-transferase and microsomal epoxide hydrolase toward benzo[a]pyrene-4,5-oxide as a substrate. These enzymes are important in the biotransformation of many epoxide xenobiotics, including potentially carcinogenic arene oxides. 

James MO, Bowen ER, Dansette PM, Bend JR (1979a) Epoxide hydrase and glutathione S-transferase activities with selected alkene and arene oxides in several marine species. Chem Biol Interact 25 321-344... 

Epoxides of aromatic rings (arene oxides) rearrange to phenols and are substrates for glutathione-S-epoxide transferase to give glutathione conjugates, the precursors of mercapturic acids (Boyland and Williams 1965). 

Cytosolic Glutathione S-Transferases in Various Rat Tissues Differ in Stereoselecdvity with PolycycEc Arene and Alkene Oxide Substrates, Drug Metab. Disposition, 14 303-309. 

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